Polymorph forms of n-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-1yl)acetamide

ABSTRACT

The invention relates to novel polymorph crystal forms A and B of N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide:  
                 
 
     The compounds and pharmaceutical compositions thereof are useful for activating a malfunctioned cholinergic neuron that is associated with memory loss disturbances.

TECHNICAL FIELD

[0001] The invention relates to novel polymorph crystal forms ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide and activation of a malfunctioned cholinergic neurontherewith.

BACKGROUND ART

[0002] Many compounds are known to treat disturbances of memory thatoccur in certain biological disorders. For example, the memory loss inAlzheimer's disease or senile dementia is associated with a malfunctionof a cholinergic neuron. Therapies pertaining to alleviating such memoryloss include attempts to increase the acetylcholine content in the brainby using an anti-acetylcholinesterase (see, e.g., Japanese PatentDocuments 61-148154, 63-141980, 63-225358, 63-238063, 63-239271,63-284175, 63-297367, 64-73 and 1-132566, European Patent ApplicationEP-A-268871, and International (PCT) Published Application WO 88/02256).

[0003] U.S. Pat. No. 5,397,785 discloses a class of 4-acylaminopyridinederivatives that activate malfunctioned cholinergic neurons. Compoundsand acid addition salts thereof disclosed in the '785 patent arebelieved to improve disturbances of memory by a different mechanism thanconventional compounds known to have anti-acetylcholinesterase activity.However, of all the compounds disclosed therein, the '785 patentprovides no discussion regarding polymorphs of any of the compounds.

[0004] The ability of a substance to crystallize with more than onecrystal structure is known as polymorphism, and a particular crystalform is called a polymorph. Different polymorphs of the same compoundcan have quite different physical properties, such as shelf-life andsolubility. Some of these differences in physical properties can lead todifferences in efficacy.

[0005] Because of these differences, it is useful to know whichparticular polymorph or mixture of polymorphs is being used.

[0006] Unfortunately, the detection of various polymorph forms of asingle drug substance is not always readily discemable. Moreover, once aspecific polymorph is recognized and desired for its characteristics,researchers must discover how to prepare consistently pure quantities ofthe polymorph form. Methods of preparing pure forms of a polymorph arenot trivial and can require intensive discovery efforts.

[0007] Therefore, a pure or essentially pure polymorph of a compound isdesirable from the standpoint of being able to accurately characterizethe physical properties and biological efficacy against certain diseasestates, such as, for example, a malfunctioned cholinergic neuronassociated with memory loss. Moreover, methods that allow for theproduction of not just one pure polymorph, but two polymorphs of acompound, also are desirable. The invention provides such polymorphcompounds and methods related thereto.

DISCLOSURE OF INVENTION

[0008] The invention relates to two novel pure or essentially purecrystal forms ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideof formula (I):

[0009] (hereinafter referred to as the form A crystal and the form Bcrystal).

[0010] The form A crystal is characterized by one or more of thefollowing: (a) a melting point (extrapolated onset) obtained from adifferential scanning calorimetry curve lower than 220° C., particularlya melting point (extrapolated onset) obtained from a differentialscanning calorimetry curve of about 217.6° C., (b) a peak at X-raydiffraction angle, 2θ, of 9.8° (±0.2°), (c) the absence of a peak atX-ray diffraction angle, 2θ, of 7.3° (±0.2°), (d) a water solubility oflower than 0.5 mg/mL, particularly a water solubility of about 0.35mg/mL, and (e) greater stability in storage than the form B crystal.

[0011] The form B crystal is characterized by one or more of thefollowing: (a) a melting point (extrapolated onset) obtained from adifferential scanning calorimetry curve higher than 220° C.,particularly a melting point (extrapolated onset) obtained from adifferential scanning calorimetry curve of about 222.6° C., (b) a peakat X-ray diffraction angle, 2θ, of 7.3° (±0.2°), (c) the absence of apeak at X-ray diffraction angles, 2θ, of 9.8° (±0.2°), (d) a watersolubility of higher than 0.5 mg/mL, particularly a water solubility ofabout 0.73 mg/mL, and (e) a worse stability in storage than the form Acrystal.

[0012] The invention also provides a pharmaceutical bulk comprisingeither the form A crystal or the form B crystal. Moreover, the inventionprovides a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and either the form A crystal or the form B crystal.

[0013] The compounds and pharmaceutical compositions thereof are usefulfor activating a malfunctioned cholinergic neuron that is associatedwith disturbances of memory loss in mammals, particularly a human. Theinvention provides for uses of the compounds and pharmaceuticalcompositions for that purpose.

[0014] The invention further provides methods of preparing pure oressentially pure quantities of the form A crystal and the form B crystalwith good reproducibility using a physiologically compatible solvent.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015]FIG. 1 shows powder X-ray diffraction curves of the form A crystal(FIG. 1-a) and the form B crystal (FIG. 1-b).

[0016]FIG. 2 shows infrared (IR) absorption spectroscopy patterns of theform A crystal and the form B crystal.

[0017]FIG. 3 shows differential scanning calorimetry (DSC) curves of theform A crystal and the form B crystal.

[0018]FIG. 4 shows solubility patterns of the form A crystal and theform B crystal.

BEST MODE FOR CARRYING OUT THE INVENTION

[0019] This invention results in two kinds of a specific pure oressentially pure crystal form of the compoundN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide:the form A crystal and the form B crystal. The compoundN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide,which is represented by the following chemical formula (I):

[0020] is a known compound disclosed in U.S. Pat. No. 5,397,785 (the'785 patent). Particulars about its preparation and its physicalproperties are found in Example 25 in the '785 patent. However, thisexample provides only the melting point of the powder obtained byrecrystallizing crude crystals from a chloroform-ethyl acetate mixture.The '785 patent provides no information about which preparations yieldwhich form of crystals or whether the compound has polymorphs or not.Moreover, when it is applied to human bodies as a medicament, it is lesspreferable halogenated solvents such as chloroform are used duringpreparation.

[0021] It has been surprisingly found that the preparation ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideby the '785 patent method results in a mixture of several forms ofcrystals in a proportion that varies depending on the preparationconditions. Therefore, the existence of various polymorph forms isvirtually impossible to discern based on the method in the '785 patent.

[0022] The form A crystal is characterized by one or more of thefollowing: (a) a melting point (extrapolated onset) obtained from adifferential scanning calorimetry curve lower than 220° C., desirably inthe range of about 213-220° C., preferably in the range of about215-220° C., more preferably in the range of about 216-218° C., mostpreferably about 218° C., and particularly about 217.6° C., (b) at leastone peak in the X-ray diffraction spectrum at diffraction angle, 2θ, of8.7°, 9.8°, 11.4°, 13.3°, 15.5°, 16.8°, and/or 17.6° ( ±0.2° ,respectively), preferably at least one peak in the X-ray diffractionspectrum at diffraction angle, 2θ, of 9.8° (±0.2°), (c) the absence of apeak (taking into account baseline noise and variations amonginstruments) at X-ray diffraction angle, 2θ, of 7.3°, 9.3°, 11.90,and/or 14.8° (±0.2°, respectively), (d) a water solubility (at 25° C.)of lower than 0.5 mg/mL, desirably in the range of about 0.1-0.5 mg/mL,preferably in the range of about 0.2-0.45 mg/mL, more preferably in therange of about 0.3-0.4 mg/mL, and particularly about 0.35 mg/mL, and (e)a better stability at room temperature (i.e., about 25° C.) and duringstorage (i.e., over time) than the form B crystal.

[0023] The form B crystal is characterized by one or more of thefollowing: (a) a melting point (extrapolated onset) obtained from adifferential scanning calorimetry curve higher than 220° C., desirablyin the range of about 220-225° C., preferably in the range of about221-224° C., more preferably in the range of about 222-223° C., mostpreferably about 223° C., and particularly about 222.6° C., (b) at leastone peak in the X-ray diffraction spectrum at diffraction angle, 2θ, of7.3°, 9.3°, 11.9°, 13.5°, 14.8°, 15.9°, 17.5°, and/or 18.6° (±0.2°,respectively), preferably at least one peak in the X-ray diffractionspectrum at diffraction angle, 2θ, of 7.3° (±0.20 ), (c) the absence ofa peak (taking into account baseline noise and variations amonginstruments) at X-ray diffraction angle, 2θ, of 8.7°, 9.8°, and/or 16.8°(±0.2°, respectively), (d) a water solubility (at 25° C.) of higher than0.5 mg/mL, desirably in the range of about 0.5-1 mg/mL, preferably inthe range of about 0.6-0.9 mg/mL, more preferably in the range of about0.7-0.8 mg/mL, and particularly about 0.73 mg/mL, and (e) a worsestability at room temperature (i.e., about 25° C.) and during storage(i.e., over time) than the form A crystal.

[0024] The invention, therefore, provides a stable, pure or essentiallypure, crystal form A or B, particularly of a pharmaceutical bulk of thecompound, to ensure standardized quality and invariable efficacy. Inother words, the invention provides pure crystal form A or B of apharmaceutical bulk of the compound that can be prepared with goodreproducibility by using a physiologically compatible solvent, such as,preferably, ethanol, water, or a mixture thereof. The use of chloroformis not required to prepare the polymorphs A and B. Therefore, the form Acrystal and form B crystal are more useful as a pharmaceutical bulk oran active ingredient of a medicament than the known compound disclosedin Example 25 of U.S. Pat. No. 5,397,785 since less preferablehalogenated solvents such as chloroform can be avoided duringpreparation.

[0025] The term “essentially pure” implies that either the form Acrystal or the form B crystal contains less than 10 wt. % of the otherpolymorph form, preferably contains less than 5 wt. % of the otherpolymorph form. Ideally, the aforementioned percentages refer to anyother polymorph form to the extent there may exist polymorph forms otherthan form A and form B as described herein.

[0026] The novel crystal forms ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideas described herein can be prepared by the following method. The form Acrystal and the form B crystal can be obtained from a solution with theproper supersaturability ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide.The form A crystal can be prepared from such a solution where thesupersaturability is less than about 5. The form B crystal can beprepared from such a solution if the supersaturability is more thanabout 20. The supersaturability can be calculated by the methoddescribed in Example 5.

[0027] The form A crystal can be prepared from a solution ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideby, for example, (a) recrystallizing slowly (the precise time framedepends on the scale of the reaction, from several hours to severaldays) and/or (b) convert form B crystals into form A crystals bystirring the suspension slowly (the precise time frame depends on scaleof the reaction, from several hours to several days). The form B crystalcan be prepared from a solution ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideby, for example, dissolving crude crystal in a solvent, with heating,followed by cooling to a temperature less than room temperature (i.e.,less than 25° C).

[0028] The process of the preparation of the form A and form B crystalsofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinomin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidecan use solvents that are safe with respect to the human body (e.g.,pharmaceutically, pharmacologically, and/or physiologically acceptable),such as water and/or solvents of which the permitted daily exposure(“PDE”) are over 10 mg/day according to the “ICH Guideline for ResidualSolvents Q3C,” preferably water and/or Class 3 solvents in the “ICHGuideline for Residual Solvents Q3C” such as acetic acid, acetone,anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether,cumene, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethylformate, formic acid, heptane, isobuthyl acetate, isopropyl acetate,methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methylisobuthyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol,2-propanol, and propyl acetate.

[0029] The invention further provides a pharmaceutical compositioncomprising a pharmaceutically acceptable (e.g., physiologicallyacceptable or pharmacologically compatible) carrier and the form A orform B crystal. Similarly, the invention provides a therapeutic agent(e.g., an anti-dementia agent) or medicament comprising the form A orform B crystal, especially for the treatment of the diseases, disorders,or conditions described herein.

[0030] The form A crystal and the form B crystal of the invention areable to activate a malfunctioned cholinergic neuron. The crystal formsof the invention (and pharmaceutical compositions thereof), therefore,are useful in a method of activating a malfunctioned cholinergic neuronin a mammal, particularly a human, with a disease. By activating thecholinergic neuron in a mammal (e.g., a human) with a compound orcomposition of the invention, the mammal's disease is effectivelytreated or prevented. Examples of diseases that involve a malfunctionedcholinergic neuron include senile dementia; dementia caused byAlzheimer's disease, Huntington's disease, Pick's disease, Down'ssyndrome or Parkinson's disease; tardive dyskinesia; myasthenia gravis;glaucoma; or somnipathy.

[0031] When the form A crystal or the fonm B crystal of the invention isused as a medicament, its route of administration is not particularlylimited, i.e., any suitable administrative route can be utilized. Thus,it can be administered either orally or parenterally. The medicament ofthe invention can be administered to patients while remaining theaforesaid crystal form. However, it is preferably administered as apharmaceutical composition containing the active ingredient andadditives, which are pharmaceutically acceptable (e.g.,pharmacologically compatible). Pharmaceutically acceptable carriers arewell known. The choice of carrier will be determined, in part, both bythe particular composition and by the particular method used toadminister the composition. Accordingly, there are a wide variety ofsuitable formulations of the pharmaceutical compositions of theinvention. Although more than one route can be used to administer aparticular composition, a particular route can provide a more immediateand more effective reaction than another route.

[0032] Pharmaceutically acceptable additives can be employed, such asvehicles, disintegrators, disintegrating aids, binders, lubricants,coating agents, pigments, diluents, bases, dissolving agents, dissolvingaids, isotonizing agents, pH regulators, stabilizers, propellants, andadhesives.

[0033] Examples of preparations suitable for oral administration includetablets, capsules, powders, fine granules, granules, solutions andsyrups. Examples of preparations suitable for parenteral administrationinclude injections, drops, ointments, creams, percutaneously absorbingagents, eye drops, ear drops, inhalants and suppositories. Theformulations can be presented in unit-dose or multi-dose sealedcontainers, such as ampules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example, water, for injections, immediatelyprior to use. However, the form of the preparation of the pharmaceuticalcomposition is not restricted to those recited herein.

[0034] Additive vehicles can be added the preparations suitable for oraladministration. Suitable additives vehicles include glucose, lactose,D-mannitol, starch and crystalline cellulose; disintegrators ordisintegrating aids such as carboxymethyl cellulose, starch andcarboxymethyl cellulose calcium salt; binders such as hydroxypropylcellulose, hydroxypropylmethyl cellulose, poly (vinyl pyrrolidone) andgelatin; lubricants such as magnesium stearate and talc; coating agentssuch as hydroxypropylmethyl cellulose, saccharose, polyethylene glycoland titanium oxide; and bases such as Vaseline, liquid paraffin,polyethylene glycol, gelatin, kaolin, glycerin, purified water and hardfat. Typical additives for preparations suitable for injections or eyedrops include dissolving agents or dissolving aids that can constituteaqueous or dissolved-before-use injections such as distilled water forinjection, physiological saline solutions and propylene glycol;isotonizing agents such as glucose, sodium chloride, D-mannitol andglycerin; pH regulators such as inorganic acids, organic acids,inorganic salts, and organic salts.

[0035] The dosage of the medicament of the invention should beappropriately increased or decreased depending on the disease, thepurpose of the treatment (e.g., prevention or treatment), and theconditions of the patient such as age, weight, and symptoms. However, ingeneral, the daily dosage for an adult patient by oral administration isabout 0.05-500 mg per day. In general, the aforesaid dosage can beadministered one time, several times everyday, or every several days.

[0036] The invention described herein also is described in JapanesePatent Application No. 121681/2001 and Japanese Patent Application No.121682/200], to which priority is claimed. The invention may be furtherunderstood by reference to the following. references: Chaki et al.,Bioorganic & Medical Chemistry Letters, 5(14), 1489-1494 (1995); Chakiet a]., Bioorganic & Medical Chemistry Letters, 5(14), 1495-1500 (1995);Bessho et al., Arznein.Forsh./Drug Res., 46(I), 369-373 (1996); Murai etal., J. Neuron. Transm. [GenSect], 98, 1-13 (1994); and Akaike et al.,Jpn. J. Pharmacol., 76, 219-222 (1998).

Examples

[0037] The following examples further illustrate the invention but, ofcourse, should not be construed as in any way limiting its scope.

[0038] Example 15 of '785 patent: Synthesis of2-(2-oxopyrrolidin-1-yl)-N-(3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-4-yl)acetamide

[0039] Into a suspension of 1.26 g of sodium hydride (60% content) in 15ml of N-ethylpyrrolidone, was added 3.28 g of 4-amino-3-methyl.-5,6,7,8-tetrahydrothieno[2,3-b]quinoline at room temperature. Themixture was heated to 50.degree. C. and stirred for 40 minutes.Thereafter, 4.72 g of methyl 2-oxo-1-pyrrolidine acetate was addeddropwise to the mixture at 50.degree. C. over a period of 30 minutes.After the stirring at 50.degree. C. for 20 minutes, the mixture wascooled to 15.degree. C. and poured into 130 ml aqueous solutioncontaining 13.5 g of ammonium chloride. After extraction of the solutionwith 100 ml of chloroform, the extract was dried over anhydrous sodiumsulfate, followed by evaporation to dryness. The resultant product wasadded with ethyl acetate, pulverized and filtered. The crude crystalswere recrystallized from chloroform-ethyl acetate to obtain 4.31 g ofthe titled compound having the melting point of 244.degree. to246.degree. C.

[0040] Example 25 of '785 patent

[0041]N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidewas synthesized in the same way as in Example 15. Melting Point (°C.):213-215

[0042] Reference Example 1: Replication of Example 25 of U.S. Pat. No.5,397,785

[0043] This example describes the replication of Example 25 of U.S. Pat.No. 5,397,785 to prepareN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide.

[0044]N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidewas prepared in the same way as in Example 25 of U.S. Pat. No. 5,397,785by recrystallizing crude crystals of the substance from achloroform-ethyl acetate mixture. The melting point of the resultantsubstance was measured by a Yanagimoto Micro Melting Point Apparatus. Inparticular, the resultant substance was put between the glass plates ofthe apparatus, which were placed on the hot plate of the apparatus andthen heated to determine the temperature at which the resultantsubstance melted. The melting point was determined to be 213-215° C. Thepreparations in the same way were repeated, however, the X-raydiffraction patterns of the resultant substances were not reproducible.

[0045] Example 1: Preparation of Forrn A Crystal Material

[0046] This example describes the preparation of the form A crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide.

[0047] 500 mg ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideprepared by the method disclosed in Example 25 of U.S. Pat. No.5,397,785 were dissolved in a mixed solvent of 4 ml of ethanol and 5 mlof water by heating to 70° C. To the solution was added 6 ml of water,and the resulting mixture was stirred at room temperature for 2 hours.The resulting crystals were filtered, washed with water, and then dried,resulting in 440 mg of the form A crystals. The melting point wasmeasured by the same method set forth in Reference Example 1 anddetermined to be 216-218° C.

[0048] Example 2: Preparation of Form B Crystal Material

[0049] This example describes the preparation of the form B crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide.

[0050] 8.8 kg of crude crystals of the compound prepared by the methoddisclosed in Example 25 of U.S. Pat. No. 5,397,785 were dissolved in55.7 kg of ethanol with heating. Floating dust was removed by hotfiltration, and then 87 L of water was added to the filtrate. Afterevaporation of the mixture to remove 27 L of the solvent under reducedpressure, 104 L of water was added, and the solution was left to standovernight. The resulting crystals were filtrated off, washed with water,and then dried, resulting in 7.5 kg of the form B crystals. The meltingpoint was measured by the same method set forth in Reference Example 1and determined to be 221-224° C.

[0051] Example 3: Preparation of Single Crystal of Form A

[0052] This example describes the preparation of single crystal of theform A crystal. 11 mg of the form A crystal obtained in Example 1 wasadded with acetonitrile, and the mixture was left standing at roomtemperature for seven weeks to obtain a transparent and colorless singlecrystal (0.3 mm×0.05 mm×0.02 mm). The intensity of the resulting singlecrystal was measured by X-ray two axes diffractometer (SMART 1000, MoK α50kV, 40mA), and then the structure was characterized according to thedirect method by conducting the high precision structure analysis basedon the full-matrix method of least squares.

[0053] Crystallographic data:

[0054] Formula: C₁₉H₂₃N₃O₃

[0055] Lattice constant: a 20.92(3) Å, b 4.805(6) Å, c 33.94(4) Å

[0056] Volume: 3413(7) Å³

[0057] Space Group: Pna2₁

[0058] Z: 8

[0059] Dx: 1.403 g/cm³

[0060] On the basis of the crystal structure, the powder pattern wassimulated to confirm that the resulting single crystal was the form Acrystal.

[0061] Example 4: Preparation of Single Crystal of Form B

[0062] This example describes the preparation of single crystal of theform B crystal. 1.5 mg of the form A crystal obtained in Example 1 wasadded with a mixed solvent of 100 μL of ethanol and 20 μL of propanol.The mixture was left standing in a refrigerator for a day to obtain atransparent and colorless single crystal (0.2 mm×0.08 mm×0.02 mm). Theintensity of the resulting single crystal was measured by X-ray two axesdiffractometer (SMART 1000, MoK α 50kV, 40 mA ), and then the structurewas characterized according to the direct method by conducting the highprecision structure analysis based on the full-matrix method of leastsquares.

[0063] Crystallographic data:

[0064] Formula: C₁₉H₂₃N₃O₃

[0065] Lattice constant: a 4.751(5) Å, b 23.87(3) Å, c 15.52(2) Å

[0066] Volume: 1757(3) Å³

[0067] Space Group: P 2₁/c

[0068] Z: 4

[0069] Dx: 1.291 g/cm³

[0070] On the basis of the crystal structure, the powder pattern wassimulated to confirm that the resulting single crystal was the form Bcrystal.

[0071] Example 5: Determination of Form A Crystal Supersaturability

[0072] 0.5 g of crude crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideprepared by the method disclosed in Example 25 of U.S. Pat. No.5,397,785 were dissolved in 5 mL of methanol to reflux with heating, towhich was added 3.3 mL of water and then left standing at roomtemperature overnight (21.5 hours). The crystals that formed werefiltrated off, and any remaining liquid was evaporated under a reducedpressure at 40° C. for 2 hours, resulting in 0.17 g of the formn Acrystals.

[0073] The supersaturability of the form A crystals was calculated asfollows: The supersaturability (calculation) is equal to theconcentration of the dissolvingN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidedivided by the solubility ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideunder the condition of crystallization.

[0074] The concentration of the dissolvingN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideis equal to the weight of N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide divided by thetotal volume of solvents of crystallization.

[0075] The solubility ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideunder the condition of crystallization refers to the solubility ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidein the solvents used in crystallization at about room temperature.

[0076] Accordingly, the supersaturability of the form A crystals wascalculated as follows:

[0077] Concentration of the dissolvingN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide=500mg/(5 mL+3.3 mL)=60.24 mg/mL Solubility ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideunder the condition of crystallization (solubility ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide in 60% methanolused as the solvent of crystallization at about room temperature)=28.05mg/mL

[0078] Supersaturability (calculation)=60.24 mg/mL/28.05 mg/mL=2.1

[0079] Example 6: Determination of Form B Crystal Supersaturability

[0080] 0.5 g of crude crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-]-yl)acetamideprepared by the method disclosed in Example 25 of U.S. Pat. No.5,397,785 were dissolved in 5 mL of methanol to reflux with heating, towhich was added 45 mL of water and then left standing at roomtemperature for 2.5 hours. The crystals that forned were filtrated off,and any remaining liquid was evaporated under reduced pressure at 40 CCfor 2 hours, resulting in 0.4 g of the form B crystals.

[0081] The supersaturability of the form B crystals was calculated inthe same manner as set forth in Example 5.

[0082] Concentration of the dissolvingN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-]-yl)acetamide=500mg/(5 mL +45 mL)=10 mg/iiL Solubility ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideunder the condition of crystallization (solubility of N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidein 10% methanol used as the solvent of crystallization at about roomtemperature)=0.41 mg/mL

[0083] Supersaturability (calculation)=10 mg/inL/0.41 mg/mL=24.4

[0084] Example 7: Conversion of Form B Crystal to Form A Crystal

[0085] A suspension was prepared by adding 0.5 g of form B crystals ofN-(2,3-dimethyl-5 ,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide to 10 mL ofwater. The suspension was stirred for 24 hours, and then the filtratingoff resulted in the form A crystals. The powder X-ray diffractionpattern of the resulting crystals was measured to confinr that theresulting crystals were form A crystals.

[0086] Example 8: Form A and Form B Crystal Characteristics

[0087] This example describes the characteristics of crystal forms A andB.

[0088] (1) Powder X-ray Diffraction Analysis (XRD)

[0089] The powder X-ray diffraction patterns of the form A crystal andthe form B crystal were measured under the following conditions:

[0090] Diffractometer: PHILIPS PW1700

[0091] Target: Cu

[0092] Monochro.: Graphite

[0093] Tube Voltage: 40 kV

[0094] Tube Current: 30 mA

[0095] Divergence Slit: 1°

[0096] Receiving Slit: 0.2 mm

[0097] Scatter Slit: 1°

[0098] Range: 3-40° 2θ

[0099] The powder X-ray diffraction patterns of the form A crystal andthe form B crystal are shown in FIG. 1. The pattern of the form A isshown in FIG. 1-a and the pattern of the form B is shown in FIG. 1-b.

[0100] The most characteristic peak of the form A crystal is thatappearing at diffraction angles, 2θ, of 9.8° (±0.2°). The particularlycharacteristic peaks of the form A crystal are those appearing atdiffraction angles, 2θ, of 8.7°, 9.8°, and 16.8° (±0.2° respectively).The characteristic peaks of the form A crystal are those appearing atdiffraction angles, 2θ, of 8.7°, 9.8°, 11.4°, 13.3°, 15.5°, and 16.8°(±0.2° respectively). The main peaks are those appearing at diffractionangles, 2θ, of 8.7°, 9.8°, 11.4°, 13.3°, 15.5°, 16.8°, and 17.6° (±0.2°,respectively). All of the peaks are those appearing at diffractionangles, 2θ, of 5.1°, 8.7°, 9.8°, 11.4°, 13.3°, 15.5°, 16.8°, 17.6°, and18.9° (±+0.2°, respectively).

[0101] The most characteristic peak of the form B crystal is thatappearing at diffraction angles, 2θ, of 7.30 (±0.2°). The particularlycharacteristic peaks of the form A crystalare those appearing atdiffraction angles, 2θ, of 7.30, 9.3°, and 11.90 (±0.20 respectively).The characteristic peaks of the form B crystal are those appearing atdiffraction angles, 2θ, of 7.3°, 9.3°, 11.9°, and 14.8° (±0.2°,respectively). The main peaks are those appearing at diffraction angles,2θ, of 7.3°, 9.3°, 11.9°, 13.5°, 14.8°, 15.9°, 17.5°, and 18.6° (±0.2°,respectively). All of the peaks are those appearing at diffractionangles, 2θ, of 7.3°, 9.3°, 11.3°, 11.9°, 13.5°, 14.8°, 15.9°, 17.5°,18.6°, and 19.4° (±0.2°, respectively).

[0102] (2) Infrared Absorption Spectroscopy Analysis (IR)

[0103] The infrared absorption spectroscopy patterns of the form Acrystal and the form B crystal were measured using KBr pellets under thefollowing conditions:

[0104] Infrared spectrometer: Paragon 1000 FTIR (Perkin-Elmer)

[0105] Sensitivity: 2.0 cm⁻¹

[0106] Range: 4000-400 cm⁻¹

[0107] The infrared absorption spectroscopy patterns of the form Acrystal and the form B crystal are shown in FIG. 2.

[0108] (3) Differential Scanning Calorimetry Analysis (DSC)

[0109] Each sample (2 mg each) of the fonr A crystal and the form Bcrystal was placed on a differential scanning calorimetry meter DSC6200R(Seiko Instruments), and the measurement was performed with a heatingrate of 20° C./minute (40-250° C., N₂ 40 ml/minute).

[0110] The differential scanning calorimetry curves of the form Acrystal and the form B crystal are shown in FIG. 3. The melting point(extrapolated onset) of the form A crystal was 490.7 K (217.6° C.), andthe heat of melting was 37.7 kJ/mol. The melting point (extrapolatedonset) of the form B crystal was 495.7 K (about 222.6° C.), and the heatof melting was 34.0 kJ/mol.

[0111] Example 9: Form A and Form B Crystal Stability and SolubilityCharacteristics

[0112] Saturated solutions of the form A crystals and the form Bcrystals were prepared at room temperature (25° C.). The concentrationsofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidein each of the saturated solutions then was measured to obtain the watersolubility of the form A and form B crystals.

[0113] About 20 mg of the form A crystal was weighed and put intoseparate tube with screwcap, then 10 mL of water were added, and thetube was capped. The tube was ultrasonicated for 5 minutes to suspendthe sample. The tube then was shaken for 3 hours in an incubator, withthe shaker setting at an appropriate temperature to obtain a saturatedsolution. The saturated solutions were filtrated using a Chromatodisk25A (GL Science). 5 mL of the filtrate were measured, and 5 mL of theinternal standard solutions (16 mg of isopropyl p-hydroxybenzoate wereweighed, and 50% methanol was added to obtain 100 mL of an internalstandard solutions) were added, and then 50% methanol was added toobtain 50 mL of sample solutions. 20 mg of each crystals were weighed,and then methanol was added to obtain 50 μL solutions. 5 mL of theaforementioned solutions were measured, and then 5 μL of the internalstandard solutions were added, and then 50% of methanol was added toobtain 50 mL of the standard solutions. 10 μL of each sample solutionand the standard solutions were subjected to liquid chromatography (LC)under the following conditions, and the following calculations werecarried out to obtain the saturated solubility of each crystal.

[0114] Saturated solubility (mg/mL)=Qt/Qs×Ws×1/50

[0115] Qt: A ratio of a peak area of each crystal for a peak area of theinternal standard in each sample solution

[0116] Qs: A ratio of a peak area of the form A crystal for a peak areaof the internal standard in the standard solutions

[0117] Ws: Sample (mg) of the standard sample of each crystal

[0118] Conditions of LC:

[0119] LC6A Liquid Chromatograph Systems (Shimazu)

[0120] Detector: Ultraviolet spectroscopy (272 nm)

[0121] Column: L-Column (4.6×250 mm)

[0122] Column Temperature: 40° C.

[0123] Eluent: mixed solvent of methanol/0.02 M ammonium acetate (60:40)

[0124] Flow rate: 0.8 mL/minute

[0125] The solubility pattern of each crystal is shown in FIG. 4. Thesolubility of the form A crystal at 25° C. is 0.35 mg/mL, and thesolubility of the form B crystal at 25° C. is 0.73 mg/mL. The form A ismore stable at room temperature (25° C.) than the form B crystal, whilethe.solubility of the form B crystal is higher than the solubility ofthe form A crystal at 25° C. and over a relatively wide temperaturerange.

INDUSTRIAL APPLICABILITY

[0126] The form A crystal and the form B crystal of the presentinvention can be prepared with good reproducibility by using solventssafe for human bodies (e.g., pharmaceutically, pharmacologically, and/orphysiologically acceptable). Therefore, it is far more useful as apharmaceutical bulk or an active ingredient of a medicament.Furthermore, the form A crystal is extremely stable in wide temperatureincluding room temperature and also has good stability during storage.The form B crystal has good solubility.

[0127] All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

[0128] The use of the terms “a” and “an” and “the” and similar referentsin the context of describing the invention (especially in the context ofthe following claims) are to be construed to cover both the singular andthe plural, unless otherwise indicated herein or clearly contradicted bycontext. The tenns “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

[0129] Preferred embodiments of this invention are described herein,including the best mode known to the inventors for carrying out theinvention. Variations of those preferred embodiments may become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventors expect skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced othenvise than as specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

1. A form A crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidine-1-yl)acetamidecharacterized at least one of the following: (a) a melting point(extrapolated onset) obtained from a differential scanning calorimetrycurve lower than 220° C., (b) at least one peak in the X-ray diffractionspectrum at diffraction angle, 2θ, of 8.7°, 9.8°, 11.4°, 13.3°, 15.5°,16.8°, and/or 17.6° (±0.2°, respectively), (c) the absence of a peak atX-ray diffraction angle, 2θ, of 7.3°, 9.3°, 11.9°, and/or 14.8° (±0.2°,respectively), and/or (d) a water solubility (at 25° C.) of lower than0.5 mg/mL.
 2. The form A crystal of claim 1 characterized by a meltingpoint (extrapolated onset) obtained from a differential scanningcalorimetry curve lower than 220° C.
 3. The form A crystal of claim 2characterized by a melting point (extrapolated onset) obtained from adifferential scanning calorimetry curve of about 217.6° C. 213-220° C.4. The form A crystal of claim 3 characterized by a melting point(extrapolated onset) obtained from a differential scanning calorimetrycurve of about
 5. The form A crystal of any of claims 1-4 characterizedby at least one peak in the X-ray diffraction spectrum at diffractionangle, 2θ, of 8.7°, 9.8°, 11.4°, 13.3°, 15.5°, 16.8°, and/or 17.6°(±0.2°, respectively).
 6. The form A crystal of any of claims 1-5characterized by a peak in the X-ray diffraction spectrum at diffractionangle, 2θ, of 9.8° (±0.20 ).
 7. The form A crystal of any of claims 1-6characterized by peaks in the X-ray diffraction spectrum at diffractionangles, 2θ, of 8.7° and 16.8° (±0.2° respectively).
 8. The form Acrystal of any of claims 1-7 characterized by peaks in the X-raydiffraction spectrum at diffraction angles, 2θ, of 11.4°, 13.3°, and15.5° (±0.2° respectively).
 9. The form A crystal of any of claims 1-8characterized by a peak in the X-ray diffraction spectrum at diffractionangle, 2θ, of 17.6° (±0.20 ).
 10. The form A crystal of any of claims1-9 characterized by the absence of a peak at X-ray diffraction angle,2θ, of 7.3°, 9.3°, 11.9°, and/or 14.8° (±0.2°, respectively).
 11. Theform A crystal of any of claims 1-10 characterized by the absence of apeak at X-ray diffraction angle, 2θ, of 7.3° (±0.2°).
 12. The form Acrystal of any of claims 1-11 characterized by the absence of a peak atX-ray diffraction angle, 2θ, of 9.3°) (±0.2°).
 13. The form A crystal ofany of claims 1-12 characterized by the absence of a peak at X-raydiffraction angles, 2θ, of 11.9°) and 14.8° (±0.2°, respectively). 14.The form A crystal of any of claims 1-13 characterized by a watersolubility (at 25° C.) of lower than 0.5 mg/mL
 15. The form A crystal ofclaim 14 characterized by a water solubility (at 25° C.) in the range ofabout 0.1-0.5 mg/mL.
 16. The form A crystal of claim 15 characterized bya water solubility (at 25° C.) of about 0.35 mg/mL.
 17. A form A crystalofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidine-1-yl)acetamidehaving (a) a melting point (extrapolated onset) obtained from adifferential scanning calorimetry curve lower than 220° C., (b) an X-raydiffraction spectrum at diffraction angle, 2θ, characterized by one ormore peaks selected from the group consisting of 8.7°, 9.8°, 11.4°,13.3°, 15.5°, 16.8°, and/or 17.6° (±0.2°, respectively); said X-raydiffraction spectrum being further characterized by the the absence ofpeaks at diffraction angle, 2θ, selected from the group consisting of7.3°, 9.3°, 11.9°, and/or 14.8 (±0.2°, respectively), and (c) a watersolubility (at 25° C.) of lower than 0.5 mg/mL.
 18. A form A crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidine-1-yl)acetamidehaving the X-ray diffraction spectrum substantially consistent withdiffraction angle in the X-ray diffraction spectrum of FIG. 1-a.
 19. Aform A crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidine-1-yl)acetamidehaving the differential scanning calorimetry curve substantiallyconsistent with the differential scanning calorimetry curve of FIG. 3.20. A form B crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidine-1-yl)acetamidecharacterized at least one of the following: (a) a melting point(extrapolated onset) obtained from a differential scanning calorimetrycurve higher than 220° C., (b) at least one peak in the X-raydiffraction spectrum at diffraction angle, 2θ, of 7.3°, 9.3°, 11.9°,13.5°, 14.8°, 15.9°, 17.5°, and/or 18.6° (±0.2°, respectively), (c) theabsence of a peak at X-ray diffraction angle, 2θ, of 8.7°, 9.8°, and/or16.8° (±0.2°, respectively), and/or (d) a water solubility (at 25° C.)of higher than 0.5 mg/mL.
 21. The form B crystal of claim 20characterized by a melting point (extrapolated onset) obtained from adifferential scanning calorimetry curve higher than 220° C.
 22. The formB crystal of claim 21 characterized by a melting point (extrapolatedonset) obtained from a differential scanning calorimetry curve of about220-225° C.
 23. The form B crystal of claim 22 characterized by amelting point (extrapolated onset) obtained from a differential scanningcalorimetry curve of about 222.6° C.
 24. The form B crystal of any ofclaims 20-23 characterized by at least one peak in the X-ray diffractionspectrum at diffraction angle, 2θ, of 7.3°, 9.3°, 11.9°, 13.5°, 14.8°,15.9°, 17.5°, and/or 18.6° (±0.2°, respectively).
 25. The form B crystalof any of claims 20-24 characterized by a peak in the X-ray diffractionspectrum at diffraction angle, 2θ, of 7.3° (±0.2°).
 26. The form Bcrystal of any of claims 20-25 characterized by peaks in the X-raydiffraction spectrum at diffraction angles, 2θ, of 9.3° and 11.9°(±0.2°respectively).
 27. The form B crystal of any of claims 20-26characterized by a peak in the action spectrum at diffraction angle, 2θ,of 14.8° (±0.2°).
 28. The form B crystal of any of claims 20-27characterized by peaks in the X-ray diffraction spectrum at diffractionangles, 2θ, of 13.5°, 15.9, 17.5°, and 18.6°) (±0.2°, respectively). 29.The form B crystal of any of claims 20-28 characterized by the absenceof a peak at X-ray diffraction angle, 2θ, of 8.7°, 9.8°, and/or 16.8°(±0.2θ, respectively).
 30. The fonr B crystal of any of claims 20-29characterized by the absence of a peak at X-ray diffraction angle, 2θ,of 9.8° (±0.2°).
 31. The form B crystal of any of claims 20-30characterized by the absence of a peak at X-ray diffraction angle, 2θ,of 8.7° (±0.2°).
 32. The form B crystal of any of claims 20-31characterized by the absence of a peak at X-ray diffraction angle, 2θ,of 16.8° (±0.2°).
 33. The form B crystal of any of claims 20-32characterized by a water solubility (at 25° C.) of higher than 0.5mg/mL.
 34. The form B crystal of claim 33 characterized by a watersolubility (at 25° C.) in the range of about 0.5-1 mg/mL.
 35. The form Bcrystal of claim 34 characterized by a water solubility (at 25° C.) ofabout 0.73 mg/mL.
 36. A form B crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidehaving (a) a melting point (extrapolated onset) obtained from adifferential scanning colorimetry curve higher than 220° C., (b) anX-ray diffraction spectrum at diffraction angle, 2θ, characterized byone or more peaks selected from the group consisting of 7.3°, 9.3°,11.9°, 13.5°, 14.8°, 15.9°, 17.5°, and/or 18.6° (±0.2°, respectively);said X-ray diffraction spectrum being further characterized by theabsence of peaks at diffraction angle, 2θ, selected from the groupconsisting of 8.7°, 9.8°, and/or 16.8° (±0.2°, respectively), and (c) awater solubility (at 25° C.) of higher than 0.5 mg/mL.
 37. A form Bcrystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidine-1-yl)acetamide having the X-ray diffraction calorimetry curvesubstantially consistent with diffraction angle in the X-ray diffractioncurve of FIG. 1-b.
 38. A form B crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidine-1-yl)acetamidehaving the differential scanning calorimetry curve substantiallyconsistent with the differential scanning calorimetry curve of FIG. 3.39. A pharmaceutical bulk comprising the form A crystal of any of claims1-19.
 40. A pharmaceutical bulk comprising the form B crystal of any ofclaims 20-38.
 41. A pharmaceutical composition comprising apharmaceutically acceptable carrier and the form A crystal of any ofclaims 1-19.
 42. A pharmaceutical composition comprising apharmaceutically acceptable carrier and the form B crystal of any ofclaims 20-38.
 43. A method of treating a mammal comprising administeringthe pharmaceutical composition of claim 41 to the mammal to treat and/orprevent a disease characterized by a malfunctioned cholinergic neuron inthe mammal.
 44. The method of claim 43, wherein the disease is seniledementia; dementia caused by Alzheimer's disease, Huntington's disease,Pick's disease, Down's syndrome, Parkinson's disease, tardivedyskinesia, myasthenia gravis, glaucoma, or somnipathy.
 45. A method oftreating a mammal comprising administering the pharmaceuticalcomposition of claim 42 to the mammal to treat and/or prevent a diseasecharacterized by a malfunctioned cholinergic neuron in the mammal. 46.The method of claim 45, wherein the disease is senile dementia; dementiacaused by Alzheimer's disease, Huntington's disease, Pick's disease,Down's syndrome, Parkinson's disease, tardive dyskinesia, myastheniagravis, glaucoma, or somnipathy.
 47. A method for preparing a crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidecomprising crystallizingN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidefrom a physiologically compatible solvent.
 48. The method of claim 47,wherein the crystal is of form A.
 49. The method of claim 47, whereinthe crystal is of form B.
 50. The method of claims 47-49, wherein thesolvent is selected by water and/or solvents of which the permitteddaily exposure (“PDE”) are over 10 mg/day according to the “ICHGuideline for Residual Solvents Q3C”.
 51. The method of claim 50,wherein the solvent is selected by water and/or Class 3 solvents in the“ICH Guideline for Residual Solvents Q3C”.
 52. The method of any ofclaims 47-51, wherein the solvent is ethanol and/or water.
 53. A methodfor preparing the form A of N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide comprisingpreparingN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidefrom a solution where the supersaturability is less than about
 5. 54.The method of claim 53 including the step of recrystallizing slowly (theprecise time frame depends on the scale of the reaction, from severalhours to several days).
 55. The method of claims 53 including the stepof converting the form B crystals ofN-[2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideinto the form A crystals ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideby stirring the suspension slowly (the precise time frame depends onscale of the reaction, from several hours to several days).
 56. A methodfor preparing the form B crystal ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidecomprising preparingN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamidefrom a solution where the supersaturability is more than about
 20. 57.The method of claim 56, wherein the solution ofN-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamideis dissolving crude crystal in a solvent; with heating, followed bycooling to a temperature less than room temperature (i.e., less than 25°C.).